This is the second re-submission of the competitive renewal. Accumulation of A early in AD appears to play an important role in the mechanisms of synaptic damage and neurodegeneration leading to cognitive deficits. During the previous period of funding we focused at developing new models and treatments for AD using lentiviral vectors expressing or blocking A degrading enzymes such s neprilysin (NEP). NEP might be important for AD also because its possible involvement in neuroprotection and as an interface between environment and genetic regulation of synaptic plasticity responses. NEP cleaves bioactive transmitters such as Neuropeptide Y (NPY) resulting in trophic C-terminal fragments (CTFs). In this context, we hypothesize that among other AB-degrading enzymes, NEP might be involved in neuroprotection in APP transgenic (tg) mice by regulating synaptic remodeling and neurogenesis in the hippocampus. The main objective of this collaborative competitive renewal will be to investigate the molecular mechanisms through which interactions between environment and A-degrading enzymes regulate synaptic regeneration and neurogenesis during aging and in AD. To this end we propose the following: Aim 1. To determine the A-independent effects of NEP and other A-degrading enzymes in synaptic regeneration during aging to murine models. Aim 2. To investigate the molecular mechanisms through which A-degrading enzymes regulate synaptic regeneration during aging and in APP tg models of AD. Aim 3. To investigate the combined effects of physical activity and expression of A-degrading enzymes on neurogenesis during aging and in APP tg models of AD. Aim 4. To evaluate the potention therapeutical and neuroprotective effects of NPY fragments in APP tg models of AD. In collaboration with the Cores with will perform studies of synaptic plasticity, neurogenesis and enhanced physical activity in APP tg, NEP, APP and NPY deficient mice, treated with lentiviral vectors expressing A-degrading enzymes and NPY fragments. Together, these studies might also help in develop new treatments for AD that will have the dual role of reducing accumulation of neurotoxic Ab species and promoting neurogenesis.